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Rutaecarpine Increases Anticancer Drug Sensitivity in Drug-Resistant Cells through MARCH8-Dependent ABCB1 Degradation

Tingting Zou1, Cheng Zeng1, Junyan Qu1

  • 1School of Life Sciences, Chongqing University, Chongqing 401331, China.

Biomedicines
|September 28, 2021
PubMed

Insights

Rutaecarpine reverses multidrug resistance (MDR) by reducing ABCB1 protein levels. This natural compound upregulates MARCH8, promoting ABCB1 degradation and enhancing chemotherapy effectiveness against cancer.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Pharmacology

Background:

  • Multidrug resistance (MDR) in cancer, often mediated by ABCB1 (P-glycoprotein), leads to chemotherapy failure.
  • Inhibiting ABCB1 is crucial for restoring chemotherapeutic drug efficacy.
  • Identifying novel strategies to overcome MDR is a significant clinical challenge.

Purpose of the Study:

  • To investigate the potential of rutaecarpine, a natural alkaloid, in reversing ABCB1-mediated MDR.
  • To elucidate the molecular mechanism by which rutaecarpine exerts its MDR-reversing effects.
  • To evaluate the therapeutic potential of combining rutaecarpine with conventional anticancer agents.

Main Methods:

  • Assessed rutaecarpine's ability to reverse ABCB1-mediated MDR in cancer cells.
  • Investigated the effect of rutaecarpine on ABCB1 protein and mRNA levels.
  • Identified and characterized the interaction between ABCB1 and the E3 ubiquitin ligase MARCH8.
  • Examined the impact of rutaecarpine on MARCH8 expression and its role in ABCB1 degradation.
  • Evaluated the efficacy of combination therapy in a transplanted tumor model.

Main Results:

  • Rutaecarpine demonstrated significant reversal of ABCB1-mediated MDR.
  • The reversal effect was attributed to the attenuation of ABCB1 protein levels.
  • ABCB1 was identified as a substrate of MARCH8, which promotes its ubiquitination and degradation.
  • Rutaecarpine upregulated MARCH8 protein levels, enhancing ABCB1 degradation.
  • Combination treatment with rutaecarpine and anticancer drugs showed therapeutic effects on transplanted tumors.

Conclusions:

  • Rutaecarpine effectively overcomes ABCB1-mediated multidrug resistance by promoting ABCB1 degradation via upregulation of MARCH8.
  • This study reveals a novel mechanism involving MARCH8 in regulating ABCB1 stability.
  • Co-administration of rutaecarpine with chemotherapeutic agents presents a promising strategy to enhance cancer treatment efficacy and overcome MDR.
Keywords:
ABCB1MARCH8multidrug resistance (MDR)rutaecarpineubiquitination

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